Project Summary Maternally acquired microbes may predispose to disease later in life; however, the determinants of niche establishment and their contributions to disease are poorly understood. We have developed a mouse model of vertical transmission in which the common human commensal enterotoxigenic Bacteroides fragilis (ETBF), carried by the dam, is stably established in the neonatal microbiota. Surprisingly, Bacteroides fragilis toxin (BFT), a carbohydrate-regulated metalloprotease associated with E-cadherin cleavage, is a key determinant of maternal inheritance, as BFT-deficient ETBF shows impaired persistence in weaned mice. Enteric disease in adulthood can be induced by antibiotics and is characterized by ETBF outgrowth, elevated bft expression, and loss of colonic mucus. We propose a model in which antibiotic treatment favors expansion of the mucolytic ETBF population and depletion of mucus-associated sugars, leading to bft derepression and host injury.